N-alpha-auro-mercapto-acetyl-aminophenols



patented Aug. 8, 956 1 1 2513,1521

UNITED STATES PATENT OFFICE V N-ALPHA-AURO-MERCAPTO-ACETYL- AMINOPHENOLS Mozes J uda Lewenstein, Kew-Gardens, N Y.

NoDrawing. Application December 16, 1947,

Y J Serial No. 792,099

I 4 Claims. (01. 260-430) 1 g V This invention relates to pharmaceutical com- Accordingly,- the compounds of this invention pounds and in particular is directed to compounds have the following type formula: used for the treatment of'arthritis and other disf eases. 5

In my pending application, Serial No. 376,841, 0H now Patent No. 2,451,841 granted October 19, 1948 I have described the N-alpha-auro-mercapto-acetanilide, CeH5.NH.CO.CH2.SAu, which is a'compound valuable for the treatment of arthri- .7 r

tis and other diseases. That compound, in the form of an oily suspension, is administered parenterally. It is absorbed by the body ata slow 7 rate owing to 'its low solubility'" The resulting -CO Q(Ri)(Rl) B H. gold-level in the body permits effective treatment r with hardly any of the disadvantageous side-re actions that often accompany the use of. soluble gold preparations. r a v I have felt that in some cases it is desirable to use a product which would be absorbed at a rate l NH 2C0 C(Rl)(R')'S'C0NH faster than the above mentioned compound, but wherein R and R are Selected from the group nevertheless much more slowly-than a waterof hydrogen andilower alkyl' soluble compound. a Example I It is therefore the, principal object of this in- 1 vention to provide-an improved-compound for use a pha carbamyl mercapto acetyl ammophenol having the formula in the treatment of arthritis and other diseases.

Further objects will become apparent frorn'the I 011 following description of the invention.

Th principal object may be achieved by the NH-co-oHi-s-coNH, use of the N-alpha-auro-mercapto-acetyl-amino- V phenols, and their acyl homologues', as for ex- 91 grams of monochloroacetic acid and 350 cc. ample, the corresponding N a,uro mercapto pro- 0f methanol were brought to ebullition under 1'6- pionyl and butyryl aminophenols, Th 5 flux, on the steam-cone, and '70 grams of orthopounds, which are related to the N-alpha-auwammophenol was added in small portions. The

mercapto-acetan'ilide in that the aromatic nuleus contains a hydroxyl group as'a-substituent zg i flask and filter flushed Wlth some me ano for one of the hydrogen atoms of the hen lradip y The solution was transferred to a roundbotcal, provide a faster rate of absorption than the t fl v V aforesaid auro-mercapto acetanilide on account g ask W1 h and mechamcal of the phenolic hydroxyl group. ;:These com- 40 s lrrer' and yq to ebulhtwnon the Steam? lf-'= cone. To the boiling solution, 66.5 grams of ampounds a prepare? from patent mercap' monium thiocyanatewere added in one portion tans which are derived from the corresponding and heating and Stirring Wer continued for resulting solution was treated with charcoal, fil-V alpha carbamyl mercapto compounds. These n t he thiocyanate d i li l,l t i 'v 1 a.

mercaptans and their parent carbamyl mercapto precipitate appears I compounds are valuable for their ownsproperties' T The mixture was allowed to stand in the iceas they have b u d With good results s box overnight; it was next filtered with suction toxifymg agents in acute poisoning- Th e The filter-cake was washed first with ice-cold pounds are also useful as intermediatesmthc methanol, later exhaustively with water. The p ep ion fthe N-auro-merC R y1aminoproduct, dried in.air, weighed 87 grams of Phenols. 1': theoretical).

The compound may be recrystallized from hot acetic acid, methanol, ethanol, or large volumes of approximately 0.1 N hydrochloric acid. From the latter solvent, it crystallizes as a granular powder of melting point (M. P.) 183-4 C.

Example I] N-alpha-mercapto-acetyl ortho-aminophenol having the formula itneo'o-onesrii 20 grams of the carbamyl compound described above, (the product of Example I) was treated with a mixture of 60 cc. concentrated aqueous ammonia and 60 cc. Water. The suspension was heated under reflux on the steam-cone for minutes, whereby the carbamyl-com'pound dissolved readily. The clear liquid was filtered at Example 111 N-alpha-auroneicapto acetyl-ortho-aminophenol having the formula m ce-wash 0.01 mole (5.56 grams) of potassium auribromide KAllBl'c, was dissolved in 50 cc. of 95% ethanol and reduced to the monovalent state with gaseous sulfur-dioxide. The originalpdeep reddish brown color tamed light yellowish to reddish, with simultaneous formation of a white precipitate of potassium bromide. The flask was stoppered and kept in ice for about 1 hour. The potassium bromide was next filtered off, and the filtrate poured into a solution of 2.01 grams (-1-.li'nole) of the mercapto 'compound'described al'ddve, the product of Example 11. The auroi'ner'captide separated at once as a white, flocculent precipitate. Themixture was diluted with excess water, and the gold compound collected on a summer funnel. It was washed repeatedly on th filter with water, ethanol and pentane, and driedfi'n vacuo'over P 05. d I

*Itffor'ms a greyish to yellowish powder, which decomposes at 215 C.

V 7 Example IV lifalpha carbamyl-mercapto -acety1-meta-aminophenol having the formula 245 grams of monochloroacetic acid and 1 liter of methanol were brought to ebullition on the steam-cone. 200 grams of meta-amino-phenol was added in small portions, and some charcoal was added. After filtration, the solution was brought back to the steam-cone and heated to boiling under reflux. 190 grams of ammonium thiocyanate was added, and boiling continued for 1 hour. Vigorous reaction took place. At the end of 1 hour, the mixture was cooled, and the precipitate formed removed by filtration. It consists essentially of ammonium chloride.

Concentration o'f the alcoholic mother-liquor to a small volume, and chilling, yielded the desired compound, having the formula above indicated, which was filtered with suction, washed with some ice-cold methanol, followed by careful washing with water, and dried in air. Yield, 214 grams (50% of theoretical). Crystallization from methanol containing a few drops of hydrochloric acid, from acetic acid, or from 0.1 N hydrochloric acid gave the pure compound, of M. P. 176 C.

Example V alpha mercapto-acetyl-meta-aminophenol having the formula ma-e mam-s11 V 2 4 grams of N a'lph'a 'carbamyl mercapto aeetynj'meta 'aminopheriol, the product of EX ample IV, were heated 'o'n 'the steam-cone under re ex, for 10 minutes, with a mixture of cc. con'c. aquebus ammonia and 460 cc. oi water. The compound dissolved veryre'ad'il'y. The mix-- tu W was tere d, suction, into a flask contain'ing I case-ice. The filtrate was acidified at once with a small excess of dilute hydrochloric Example VI N alpha-a um-mercapto-acetyl-meta aminophenol having the formula This com elled was prepared in accordance with {the method :used in Example III'exc'ept that the N alpha mercapto acetyl-meta aminophenol was reacted with the monovalent gold solution described in Example 111.

- The compound has a decomposition point of 237 C.

250 grams of monochloroacetic acid wasdissolved in 1.5 liters of-methanol. The solution was heated to ebullition on the steam-cone, under a refiux condenser, and 200 grams of para aminophenol were added in several portions; the mixture was refluxed, until complete solution was achieved (about 15 ,minutes). ,A -suspensi on of 175 grams of ammonium thiocyanate in 500 cc. of methanol was added, and heating was continued for 30 minutes, whereby a moderately strong reaction occurs, in the beginning. Charcoal was added next to the solution, and the suspension was filtered with suction. Crystallization of the desired compound, having the formula above indicated, was brought about by chilling of the filtrate. It was filtered with suction, washed with a small volume of ice-cold methanol, followed by thorough washing withwater. Itwas dried in air. Yield; 187 grams (45% of theoretical); Concentration of the mother-liquon-and additionof excess Water gave a second crop of about 15 grams. a I I LThe compound was purified by recrystallization from ethanol containing a few drops of hydrochloric acid, or from approximately 0.1 N hydrochloric acid, M. P. 190 C.

Example VIII N-alpha-m'e'ncapto-acetyl-para aminophenol having the formula' V Nu -o o-cm-s r 30 grams ()[f N-alpha carbamyl -...merca'ptoacetyl para aminophenol, the product of Example, VII, were heated for 20 minutes with a mixture of 90 cc. 04f concentrated aqueous ammonia and 2'70 -cc..of'water. -..The carbamyl compound rapidly went into solution. The liquid was 'fil-.- tereda-with suction into aflask containing excess ice. The filtrate was acidified immediatelywith dilute hydrochloric acid. The desired compound appeared as a white precipitate, which was kept in the refrigerator for one day. The compound was next filtered with suction, washed well with water slightly acidified with hydrochloricacid, and dried in vacuo over phosphorus pentoxide. Yield, 20 grams (83 of theoretical).

The compound was purified by recrystallization from methanol containing a small percentage of hydrochloric acid, or from water slightly acidified with hydrochloric acid. M. P. 136 0.

Example IX 6 This compound was prepared in a manner similar to the preparation of its ortho and meta isomrs, starting w'ith'l N-alp'hamercaptmacetyle para. aminophenoL'in accordance 'with'the' method described in Example III. It has a decomposition point of 238-39" C.

Example X N-alpha carbamyl; mercapto propionylortho aminophenol having the formula NH-Cb-dH-CHQ CONH2 Q o 0.1 mole (10.9 grams) o f ortho aminopher'iol, 0.15 mole (23.0 grams) of commercial alpha bromopropionic acid, and0.15 mole (12.2 rams) of sodium thiocyanate were heated to reflux on a-steam cone with 150 cc. of methanol. The mix ture was kept refluxing for one hour. In the beginning vigorous reaction occurred. The mixture was next chilled in ice, and the precipitate con-'- ErampleXI N -alpha-mercapto-propionyl-ortho aminophenol having the formula 10 grams of the N-alpha carbamyl-mercaptopropionyl ortho 'aminophenol, the product of Example X, were treated with cc. of 111mmture of concentrated aqueous ammonia and water by heating on a steam cone for 10 minutes, when the product dissolves readily. Thesolution was next filtered rapidly by suction through a Buchner funnel into a flask containing excess ice and the filtrate was at once treated with a small excess of hydrochloric acid. The N-alphamercapto-propionyl-ortho aminophenol appears as a white precipitate. It was collected on .a Buchner funnel, washed with water acidified with a few drops of hydrochloric acid, and dried in yacuo over phosphorus pentoxide.

} I Example XII N-alpha-aurormercaptopropiony1-ortho aminophenol having the formula NH-CO-(|)H -C Ha SAu This compound was prepared from; the N- alpha-mercapto-propiony1-ortho aminophenol, the product of Example XI, in accordance with the general method described in Example III for the preparation of the corresponding N- alpha-auro mercaptmacetyl-ortho amin'ophenol'.

anemia.

Example; XIII;

he ma, c r myhm capto butryl meta m nmh ly mefo m a 0.1 mole (10.9 grams) ofmeta aminophenol and 1.5 moles (25.1 grams) of alpha bromobutyric acid were heated to ebullition-withlZO cc. of ethanol on a steam cone under reflux. Then 1.5 mu e r lrem Q amm n m iqe were added; one portion, going into: solution an mfqdue ne Strong ti n The Wr-e waswkept refluxing for: minutes. A; precipitate formedlconsisting mainly of ammonium chloride wh he re d a i nd th i xeil compound,- the. Nealpha' carbamyle nercaptoe butyryl-meta 'aminophenol, obtained, from the fi t qeae i ati i ede e a t d Prefe S111?- By. analogous methods, starting with" the; an: propriate aminophenols l and alpha. loroinofatty acids, there are obtained. the. related mercapto carbamyllcompeunds such asz- N alpha-carbamyl mercapto-propiony1 meta aminophenol;

N: -Jalpha-carbamyl mercapto-prpionyl para aminophenol;

N; alphaa .carbamyl mercapto-butyryl ortho aminophenol. a

N alpha carbamyl mercapto-butyryl-para aminophenol.

N --alpha-carbamyl-mercapto -isobutyryl-ortho aminophenoll U r N alpha-carbamyl-mercaptoisobutyryl-meta aminophenol.

N alpha-carbamyl-rnercapto-isobutyryl-para aminophenol;

Example XIV N-i-alphaemercapmwutyrylameta.. aminonhenol having the:formula grams of N-alpha carbamyl rnercaptobutyryl me-ta aminophenol; the compound o f Ex: ample XIII; weretreated with 60 ccl-of a 1 21 mix ture of concentrated aqueous ammonia and wat'r by heating onasteamcorie for-1'0 minutes} the mercapto carbamyl compound dissolving readily. The solution was nextfilte'red rapidly by suction througha" Buchnerfunnel" into a flash containing excess ice and the filtrate-was at 'once treated with a small excess of hydrochloric acid. The N alpha-mercapto-butyryl-meta aminophenol appeared as a white precipitate which was collected on a Buchner'iunnelahd washed well with water acidified with a few drops of hydrochloric acid and dried in vacuo ,over phosphprus pcntoxidei, The compound may. be recrystallized 'frnm boiling. water containing a smalla 8 310 21} of hydrochloric. acid.

' In a or n i h t iome ins n ral m ca h r are; a n dree} t e e r sn ns 8. ing appropriate carbamyl mercapto compounds 3!?- QFPW EF N p a n o p onionylemeta amine: phenol.

N alpha mercapto propionyl-para aminophenol.

N-alpha-mercapto-butyry1-or;tho :aminophenol.

N-alpha-mercapto-butyry1-para aminophenol.

N alpha mercapto-isobutyryl ortho aminophenol.

N alpha mercapto-isobutyryl-meta aminophenoh, NP alpha. mereantorisobutyry epam1am no:

phenol; 4

- EWWP V N alpha-aura mercapto-isobutyryl para a ne fi x vi e e fema e N alpha -auro- -mercapto; pr0pi0ny1'.- meta aminophenoli Nzalpha auromercapto propionylipara aminophenol.

N t-alpha-allroemercapto-butyryl+ortho aminophenol: N:-alphaeauro mercapto-butyryl-meta aminophenol N alpha-aurmmercapto-butyryl para. aminophenol; N alpha- ---auro"- mercapto isobutyryl-ortho aminophenpl. i N'- alpha auro mercapto --isobutyryl para aminophenol.

1.. The N:- alpha-auro-mercapto+acetyleortho,

aminophenoh 2. The, N: alpha-auramercapto; a.c tylvmeta aminophenol.

3. The N alpha.- auro-mercapto-acetyl-para ammophenol.

'4. N'-a1pha-auro-mercapto,- acetyl, aminophe: n01, HO.CsI-I4.NH.CO.CH2-SAu.

MOZES J. (JUDA LEWENSTEIN.

(References on following page) REFERENCES CITED FOREIGN-{PATENTS The following references are of record in the Number Country Date file of this patent: 555,141 Great Britain Aug. 5, 1943 UNITED STATES PATENTS 3 OTHER REFERENCES Number Name Date Beckurts et aL, Journal fur praktische Chemie,

1,663,390 Schveller et a1 20, 1928 vol. 174 (neue folge 66) pages 172 to 193 (1902).

1,869,834 Yoshioka. Aug. 2, 1932 2,049,198 Delange July 28, 1936 2,412,700 Weissberger et a1. Dec. 17, 1946 m 

1. THE N - ALPHA-AURO-MERCAPTO-ACETYL-ORTHO AMINOPHENOL. 